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1.  Intravascular Ultrasound to Guide Percutaneous Coronary Interventions 
Executive Summary
Objective
The objective of this health technology policy assessment was to determine the effectiveness and cost-effectiveness of using intravascular ultrasound (IVUS) as an adjunctive imaging tool to coronary angiography for guiding percutaneous coronary interventions.
Background
Intravascular Ultrasound
Intravascular ultrasound is a procedure that uses high frequency sound waves to acquire 3-dimensional images from the lumen of a blood vessel. The equipment for performing IVUS consists of a percutaneous transducer catheter and a console for reconstructing images. IVUS has been used to study the structure of the arterial wall and nature of atherosclerotic plaques, and obtain measurements of the vessel lumen. Its role in guiding stent placement is also being investigated. IVUS is presently not an insured health service in Ontario.
Clinical Need
Coronary artery disease accounts for approximately 55% of cardiovascular deaths, the leading cause of death in Canada. In Ontario, the annual mortality rate due to ischemic heart disease was 141.8 per 100,000 population between 1995 and 1997. Percutaneous coronary intervention (PCI), a less invasive approach to treating coronary artery disease, is used more frequently than coronary bypass surgery in Ontario. The number of percutaneous coronary intervention procedures funded by the Ontario Ministry of Health and Long-term Care is expected to increase from approximately 17, 780 in 2004/2005 to 22,355 in 2006/2007 (an increase of 26%), with about 95% requiring the placement of one or more stents. Restenosis following percutaneous coronary interventions involving bare metal stents occurs in 15% to 30% of the cases, mainly because of smooth muscle proliferation and migration, and production of extracellular matrix. In-stent restenosis has been linked to suboptimal stent expansion and inadequate lesion coverage, while stent thrombosis has been attributed to incomplete stent-to-vessel wall apposition. Since coronary angiography (the imaging tool used to guide stent placement) has been shown to be inaccurate in assessing optimal stent placement, and IVUS can provide better views of the vessel lumen, the clinical utility of IVUS as an imaging tool adjunctive to coronary angiography in coronary intervention procedures has been explored in clinical studies.
Method
A systematic review was conducted to answer the following questions:
What are the procedure-related complications associated with IVUS?
Does IVUS used in conjunction with angiography to guide percutaneous interventions improve patient outcomes compared to angiographic guidance without IVUS?
Who would benefit most in terms of clinical outcomes from the use of IVUS adjunctive to coronary angiography in guiding PCIs?
What is the effectiveness of IVUS guidance in the context of drug-eluting stents?
What is the cost-effectiveness ratio and budget impact of adjunctive IVUS in PCIs in Ontario?
A systematic search of databases OVID MEDLINE, EMBASE, MEDLINE In-Process & Other Non-Indexed Citations, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) database for the period beginning in May 2001 until the day of the search, November 4, 2005 yielded 2 systematic reviews, 1 meta-analysis, 6 randomized controlled trials, and 2 non-randomized studies on left main coronary arteries. The quality of the studies ranged from moderate to high. These reports were combined with reports from a previous systematic review for analysis. In addition to qualitative synthesis, pooled analyses of data from randomized controlled studies using a random effect model in the Cochrane Review Manager 4.2 software were conducted when possible.
Findings of Literature Review & Analysis
Safety
Intravascular ultrasound appears to be a safe tool when used in coronary interventions. Periprocedural complications associated with the use of IVUS in coronary interventions ranged from 0.5% in the largest study to 4%. Coronary rupture was reported in 1 study (1/54). Other complications included prolonged spasms of the artery after stenting, dissection, and femoral aneurysm.
Effectiveness
Based on pooled analyses of data from randomized controlled studies, the use of intravascular ultrasound adjunctive to coronary intervention in percutaneous coronary interventions using bare metal stents yielded the following findings:
For lesions predominantly at low risk of restenosis:
There were no significant differences in preintervention angiographic minimal lumen diameter between the IVUS-guided and angiography-guided groups.
IVUS guidance resulted in a significantly larger mean postintervention angiographic minimal lumen diameter (weighted mean difference of 0.11 mm, P = .0003) compared to angiographic guidance alone.
The benefit in angiographic minimal lumen diameter from IVUS guidance was not maintained at 6-month follow-up, when no significant difference in angiographic minimal lumen diameter could be detected between the two arms (weighted mean difference 0.08, P = .13).
There were no statistically significant differences in angiographic binary restenosis rates between IVUS-guidance and no IVUS guidance (Odds ratio [OR] 0.87 in favour of IVUS, 95% Confidence Interval [CI] [0.64–1.18], P = 0.37).
IVUS guidance resulted in a reduction in the odds of target lesion revascularization (repeat percutaneous coronary intervention or coronary bypass graft) compared to angiographic guidance alone. The reduction was statistically significant at a follow-up period of 6 months to 1 year, and at a follow-up period of 18 month to 2 years (OR 0.52 in favour of IVUS, 95% CI [0.33–0.81], P = .004).
Total revascularization rate (either target lesion or target vessel revascularization) was significantly lower for IVUS-guided patients at 18 months to 2.5 years after intervention (OR 0.43 in favour of IVUS, 95% CI [0.29–0.63], p < .0001).
There were no statistically significant differences in the odds of death (OR 1.36 in favour of no IVUS, P =0.65) or myocardial infarction (OR 0.95 in favour of IVUS, P = 0.93) between IVUS-guidance and angiographic guidance alone at up to 2.5 years of follow-up
The odds of having a major cardiac event (defined as death, myocardial infarction, and target lesion or target vessel revascularization) were significantly lower for patients with IVUS guidance compared to angiographic guidance alone during follow-up periods of up to 2.5 years (OR 0.53, 95% CI [0.36–0.78], P = 0.001). Since there were no significant reductions in the odds of death or myocardial infarction, the reduction in the odds of combined events reflected mainly the reduction in revascularization rates.
For lesions at High Risk of Restenosis:
There is evidence from one small, randomized controlled trial (n=150) that IVUS-guided percutaneous coronary intervention in long de novo lesions (>20 mm) of native coronary arteries resulted in statistically significant larger minimal lumen Diameter, and statistically significant lower 6-month angiographic binary restenosis rate. Target vessel revascularization rate and the rate of combined events were also significantly reduced at 12 months.
A small subgroup analysis of a randomized controlled trial reported no benefit in clinical or angiographic outcomes for IVUS-guided percutaneous coronary interventions in patients with diabetes compared to those guided by angiography. However, due to the nature and size of the analysis, no firm conclusions could be reached.
Based on 2 small, prospective, non-randomized controlled studies, IVUS guidance in percutaneous coronary interventions of left main coronary lesions using bare metal stents or drug-eluting stents did not result in any benefits in angiographic or clinical outcomes. These findings need to be confirmed.
Interventions Using Drug-Eluting Stents
There is presently no evidence on whether the addition of IVUS guidance during the implantation of drug-eluting stents would reduce incomplete stent apposition, or improve the angiographic or clinical outcomes of patients.
Ontario-Based Economic Analysis
Cost-effectiveness analysis showed that PCIs using IVUS guidance would likely be less costly and more effective than PCIs without IVUS guidance. The upfront cost of adjunctive use of IVUS in PCIs ranged from $1.56 million at 6% uptake to $13.04 million at 50% uptake. Taking into consideration cost avoidance from reduction in revascularization associated with the use of IVUS, a net saving of $0.63 million to $5.2 million is expected. However, since it is uncertain whether the reduction in revascularization rate resulting from the use of IVUS can be generalized to clinical settings in Ontario, further analysis on the budget impact and cost-effectiveness need to be conducted once Ontario-specific revascularization rates are verified.
Factors to be Considered in the Ontario Context
Applicability of Findings to Ontario
The interim analysis of an Ontario field evaluation that compared drug-eluting stents to bare metal stents showed that the revascularization rates in low-risk patients with bare metal stents were much lower in Ontario compared to rates reported in randomized controlled trials (7.2% vs >17 %). Even though IVUS is presently not routinely used in the stenting of low-risk patients in Ontario, the revascularization rates in these patients in Ontario were shown to be lower than those reported for the IVUS groups reported in published studies. Based on this information and previous findings from the Ontario field evaluation on stenting, it is uncertain whether the reduction in revascularization rates from IVUS guidance can be generalized to Ontario. In light of the above findings, it is advisable to validate the reported benefits of IVUS guidance in percutaneous coronary interventions involving bare metal stents in the Ontario context.
Licensing Status
As of January 16, 2006, Health Canada has licensed 10 intravascular ultrasound imaging systems/catheters for transluminal intervention procedures, most as class 4 medical devices.
Current Funding
IVUS is presently not an insured procedure under the Ontario Health Insurance Plan and there are no professional fees for this procedure. All costs related to the use of IVUS are covered within hospitals’ global budgets. A single use IVUS catheter costs approximately $900CDN and the procedure adds approximately 20 minutes to 30 minutes to a percutaneous coronary intervention procedure.
Diffusion
According to an expert consultant, current use of IVUS in coronary interventions in Ontario is probably limited to high-risk cases such as interventions in long lesions, small vessels, and bifurcated lesions for which images from coronary angiography are indeterminate. It was estimated that IVUS is being used in about 6% of all percutaneous coronary interventions at a large Ontario cardiac centre.
Expert Opinion
IVUS greatly enhances the cardiac interventionists’ ability to visualize and assess high-risk lesions such as long lesions, narrow lesions, and bifurcated lesions that may have indeterminate angiographic images. Information from IVUS in these cases facilitates the choice of the most appropriate approach for the intervention.
Conclusion
The use of adjunctive IVUS in PCIs using bare metal stents in lesions predominantly at low risk for restenosis had no significant impact on survival, myocardial infarction, or angiographic restenosis rates up to 2.5 years after intervention.
The use of IVUS adjunctive to coronary angiography in percutaneous coronary interventions using bare metal stents in lesions predominantly at low risk for restenosis significantly reduced the target lesion and target vessel revascularization at a follow-up period of 18 months to 2.5 years.
One small study suggests that adjunctive IVUS in PCIs using bare metal stents in long lesions (>20 mm) significantly improved the 6-month angiographic restenosis rate and one-year target lesion revascularization rate. These results need to be confirmed with large randomized controlled trials.
Based on information from the Ontario field evaluation on stenting, it is uncertain whether the reduction in revascularization rate resulting from the use of IVUS in the placement of bare metal stents can be generalized to clinical settings in Ontario.
There is presently insufficient evidence available to determine the impact of adjunctive IVUS in percutaneous interventions in high-risk lesions (other than long lesions) or in PCIs using drug-eluting stents.
PMCID: PMC3379536  PMID: 23074482
2.  Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Pease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: an Evidence-Based Analysis
The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:
The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7
Objective
The objective of this analysis was to determine the diagnostic accuracy of cardiac magnetic resonance imaging (MRI) for the diagnosis of patients with known/suspected coronary artery disease (CAD) compared to coronary angiography.
Cardiac MRI
Stress cardiac MRI is a non-invasive, x-ray free imaging technique that takes approximately 30 to 45 minutes to complete and can be performed using to two different methods, a) perfusion imaging following a first pass of an intravenous bolus of gadolinium contrast, or b) wall motion imaging. Stress is induced pharmacologically with either dobutamine, dipyridamole, or adenosine, as physical exercise is difficult to perform within the magnet bore and often induces motion artifacts. Alternatives to stress cardiac perfusion MRI include stress single-photon emission computed tomography (SPECT) and stress echocardiography (ECHO). The advantage of cardiac MRI is that it does not pose the radiation burden associated with SPECT. During the same sitting, cardiac MRI can also assess left and right ventricular dimensions, viability, and cardiac mass. It may also mitigate the need for invasive diagnostic coronary angiography in patients with intermediate risk factors for CAD.
Evidence-Based Analysis
Literature Search
A literature search was performed on October 9, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 to October 9, 2008. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist and then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Given the large amount of clinical heterogeneity of the articles meeting the inclusion criteria, as well as suggestions from an Expert Advisory Panel Meeting held on October 5, 2009, the inclusion criteria were revised to examine the effectiveness of cardiac MRI for the detection of CAD.
Heath technology assessments, systematic reviews, randomized controlled trials, observational studies
≥20 adult patients enrolled.
Published 2004-2009
Licensed by Health Canada
For diagnosis of CAD:
Reference standard is coronary angiography
Significant CAD defined as ≥ 50% coronary stenosis
Patients with suspected or known CAD
Reported results by patient, not segment
Non-English studies
Grey literature
Planar imaging
MUGA
Patients with recent MI (i.e., within 1 month)
Patients with non-ischemic heart disease
Studies done exclusively in special populations (e.g., women, diabetics)
Outcomes of Interest
Sensitivity and specificity
Area under the curve (AUC)
Diagnostic odds ratio (DOR)
Summary of Findings
Stress cardiac MRI using perfusion analysis yielded a pooled sensitivity of 0.91 (95% CI: 0.89 to 0.92) and specificity of 0.79 (95% CI: 0.76 to 0.82) for the detection of CAD.
Stress cardiac MRI using wall motion analysis yielded a pooled sensitivity of 0.81 (95% CI: 0.77 to 0.84) and specificity of 0.85 (95% CI: 0.81 to 0.89) for the detection of CAD.
Based on DORs, there was no significant difference between pooled stress cardiac MRI using perfusion analysis and pooled stress cardiac MRI using wall motion analysis (P=0.26) for the detection of CAD.
Pooled subgroup analysis of stress cardiac MRI using perfusion analysis showed no significant difference in the DORs between 1.5T and 3T MRI (P=0.72) for the detection of CAD.
One study (N=60) was identified that examined stress cardiac MRI using wall motion analysis with a 3T MRI. The sensitivity and specificity of 3T MRI were 0.64 (95% CI: 0.44 to 0.81) and 1.00 (95% CI: 0.89 to 1.00), respectively, for the detection of CAD.
The effectiveness of stress cardiac MRI for the detection of CAD in unstable patients with acute coronary syndrome was reported in only one study (N=35). Using perfusion analysis, the sensitivity and specificity were 0.72 (95% CI: 0.53 to 0.87) and 1.00 (95% CI: 0.54 to 1.00), respectively, for the detection of CAD.
Ontario Health System Impact Analysis
According to an expert consultant, in Ontario:
Stress first pass perfusion is currently performed in small numbers in London (London Health Sciences Centre) and Toronto (University Health Network at the Toronto General Hospital site and Sunnybrook Health Sciences Centre).
Stress wall motion is only performed as part of research protocols and not very often.
Cardiac MRI machines use 1.5T almost exclusively, with 3T used in research for first pass perfusion.
On November 25 2009, the Cardiac Imaging Expert Advisory Panel met and made the following comments about stress cardiac MRI for perfusion analysis:
Accessibility to cardiac MRI is limited and generally used to assess structural abnormalities. Most MRIs in Ontario are already in 24–hour, constant use and it would thus be difficult to add cardiac MRI for CAD diagnosis as an additional indication.
The performance of cardiac MRI for the diagnosis of CAD can be technically challenging.
GRADE Quality of Evidence for Cardiac MRI in the Diagnosis of CAD
The quality of the body of evidence was assessed according to the GRADE Working Group criteria for diagnostic tests. For perfusion analysis, the overall quality was determined to be low and for wall motion analysis the overall quality was very low.
PMCID: PMC3377522  PMID: 23074389
3.  Periodontal Disease and its Association with Angiographically Verified Coronary Artery Disease 
Acta Stomatologica Croatica  2015;49(1):14-20.
Purpose
The aim of this research was to investigate the association of chronic and aggressive periodontitis with the severity of coronary artery disease which was angiographically verified.
Material and methods
Subjects were selected among the hospitalized patients at the University Hospital Centre Zagreb who had coronary angiography done because of the chest pain. Thorough clinical examination included periodontal indices and clinical and socio-demographic characteristics of participants. Subjects were divided in two test groups, acute coronary syndrome (ACS) and stable coronary artery disease (CAD), and the control group with no significant CAD. Data were analyzed using Kruskal-Wallis and Pearson’s Chi-Square test.
Results
From 106 subjects, 66 (62.3%) were hospitalized for ACS, 22 (20.7%) had stable CAD and only 18 (17.0%) had no significant CAD. Only 26 (24.5%) out of 106 patients were never smokers (p<0.05). Chronic periodontitis was the most common finding with 68.2% in ACS group and 54.5% in stable CAD group, while healthy patients without periodontitis (72.6%) were dominant in the control group (p<0.001). Stable CAD group had the highest mean probing depth (PD) 3.92±1.16, gingival recession (GR) 1.34±0.78, clinical attachment level (CAL) 4.60±1.41 and bleeding on probing (BOP) 45.98±26.19 values, whereas ACS group had mean PD value of 3.77±0.91, GR 1.11±0.66, CAL 4.32±1.08 and BOP 41.30±22.09, and no significant CAD group had mean PD value of 3.27±0.97, GR 0.69±0.37, CAL 3.62±1.04 and BOP 26.39±13.92 (p<0.05).
Conclusion
Periodontitis was shown to be associated with angiographically verified coronary artery disease. Physical inactivity, poor oral hygiene and periodontal inflammation were observed in patients with ACS and stable CAD.
doi:10.15644/asc49/1/2
PMCID: PMC4945348  PMID: 27688381
Periodontitis; Periodontal Index; Cardiovascular Diseases; Coronary Artery Disease; Coronary Angiography
4.  64-Slice Computed Tomographic Angiography for the Diagnosis of Intermediate Risk Coronary Artery Disease 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Pease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: an Evidence-Based Analysis
The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:
The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7
Objective
The objective of this report is to determine the accuracy of computed tomographic angiography (CTA) compared to the more invasive option of coronary angiography (CA) in the detection of coronary artery disease (CAD) in stable (non-emergent) symptomatic patients.
CT Angiography
CTA is a cardiac imaging test that assesses the presence or absence, as well as the extent, of coronary artery stenosis for the diagnosis of CAD. As such, it is a test of cardiac structure and anatomy, in contrast to the other cardiac imaging modalities that assess cardiac function. It is, however, unclear as to whether cardiac structural features alone, in the absence cardiac function information, are sufficient to determine the presence or absence of intermediate pretest risk of CAD.
CTA technology is changing rapidly with increasing scan speeds and anticipated reductions in radiation exposure. Initial scanners based on 4, 8, 16, 32, and 64 slice machines have been available since the end of 2004. Although 320-slice machines are now available, these are not widely diffused and the existing published evidence is specific to 64-slice scanners. In general, CTA allows for 3-dimensional (3D) viewing of the coronary arteries derived from software algorithms of 2-dimensional (2D) images.
The advantage of CTA over CA, the gold standard for the diagnosis of CAD, is that it is relatively less invasive and may serve as a test in determining which patients are best suited for a CA. CA requires insertion of a catheter through an artery in the arm or leg up to the area being studied, yet both tests involve contrast agents and radiation exposure. Therefore, the identification of patients for whom CTA or CA is more appropriate may help to avoid more invasive tests, treatment delays, and unnecessary radiation exposure. The main advantage of CA, however, is that treatment can be administered in the same session as the test procedure and as such, it’s recommended for patients with a pre-test probability of CAD of ≥80%. The progression to the more invasive CA allows for the diagnosis and treatment in one session without the added radiation exposure from a previous CTA.
The visibility of arteries in CTA images is best in populations with a disease prevalence, or pre-test probabilities of CAD, of 40% to 80%, beyond which patients are considered at high pre-test probability. Visibility decreases with increasing prevalence as arteries become increasingly calcified (coronary artery calcification is based on the Agaston score). Such higher risk patients are not candidates for the less invasive diagnostic procedures and should proceed directly to CA, where treatment can be administered in conjunction with the test itself, while bypassing the radiation exposure from CTA.
CTA requires the addition of an ionated contrast, which can be administered only in patients with sufficient renal function (creatinine levels >30 micromoles/litre) to allow for the clearing of the contrast from the body. In some cases, the contrast is administered in patients with creatinine levels less than 30 micromoles/litre.
A second important criterion for the administration of the CTA is patient heart rate, which should be less than 65 beats/min for the single source CTA machines and less than 80 beats/min for the dual source machines. To decrease heart rates to these levels, beta-blockers are often required. Although the accuracy of these two machines does not differ, the dual source machines can be utilized in a higher proportion of patients than the single source machines for patients with heart beats of up to 80 beats/min. Approximately 10% of patients are considered ineligible for CTA because of this inability to decrease heart rates to the required levels. Additional contra-indications include renal insufficiency as described above and atrial fibrillation, with approximately 10% of intermediate risk patients ineligible for CTA due these contraindications. The duration of the procedure may be between 1 and 1.5 hours, with about 15 minutes for the CTA and the remaining time for the preparation of the patient.
CTA is licensed by Health Canada as a Class III device. Currently, two companies have licenses for 64-slice CT scanners, Toshiba Medical Systems Corporation (License 67604) and Philips Medical Systems (License 67599 and 73260).
Research Questions
How does the accuracy of CTA compare to the more invasive CA in the diagnosis of CAD in symptomatic patients at intermediate risk of the disease?
How does the accuracy for CTA compare to other modalities in the detection of CAD?
Research Methods
Literature Search
A literature search was performed on July 20, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until July 20, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language articles and English or French-language HTAs published from January 1, 2004 to July 20, 2009.
Randomized controlled trials (RCTs), non-randomized clinical trials, systematic reviews and meta-analyses.
Studies of symptomatic patients at intermediate pre-test probability of CAD.
Studies of single source CTA compared to CA for the diagnosis of CAD.
Studies in which sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) could be established. HTAs, SRs, clinical trials, observational studies.
Exclusion Criteria
Non-English studies.
Pediatric populations.
Studies of patients at low or high pre-test probability of CAD.
Studies of unstable patients, e.g., emergency room visits, or a prior diagnosis of CAD.
Studies in patients with non-ischemic heart disease.
Studies in which outcomes were not specific to those of interest in this report.
Studies in which CTA was not compared to CA in a stable population.
Outcomes of Interest)
CAD defined as ≥50% stenosis.
Comparator
Coronary angiography.
Measures of Interest
Sensitivity, specificity;
Negative predictive value (NPV), positive predictive value (PPV);
Area under the curve (AUC) and diagnostic odds ratios (DOR).
Results of Literature Search and Evidence-Based Analysis
The literature search yielded two HTAs, the first published by MAS in April 2005, the other from the Belgian Health Care Knowledge Centre published in 2008, as well as three recent non-randomized clinical studies. The three most significant studies concerning the accuracy of CTA versus CA are the CORE-64 study, the ACCURACY trial, and a prospective, multicenter, multivendor study conducted in the Netherlands. Five additional non-randomized studies were extracted from the Belgian Health Technology Assessment (2008).
To provide summary estimates of sensitivity, specificity, area under the SROC curve (AUC) and diagnostic odds rations (DORs), a meta-analysis of the above-mentioned studies was conducted. Pooled estimates of sensitivity and specificity were 97.7% (95%CI: 95.5% - 99.9%) and 78.8% (95%CI: 70.8% - 86.8%), respectively. These results indicate that the sensitivity of CTA is almost as good as CA, while its specificity is poorer. The diagnostic odds ratio (DOR) was estimated at 157.0 (95%CI: 11.2 - 302.7) and the AUC was found to be 0.94; however, the inability to provide confidence estimates for this estimate decreased its utility as an adequate outcome measure in this review.
This meta-analysis was limited by the significant heterogeneity between studies for both the pooled sensitivity and specificity (heterogeneity Chi-square p=0.000). To minimize these statistical concerns, the analysis was restricted to studies of intermediate risk patients with no previous history of cardiac events. Nevertheless, the underlying prevalence of CAD ranged from 24.8% to 78% between studies, indicating that there was still some variability in the pre-test probabilities of disease within this stable population. The variation in the prevalence of CAD, accompanied with differences in the proportion of calcification, likely affected the specificity directly and the sensitivity indirectly across studies.
In February 2010, the results of the Ontario Multi-detector Computed Tomography Coronary Angiography Study (OMCAS) became available and were thus included in a second meta-analysis of the above studies. The OMCAS was a non-randomized double-blind study conducted in 3 centers in Ontario that was conducted as a result of a MAS review from 2005 requesting an evaluation of the accuracy of 64-slice CTA for CAD detection. Within 10 days of their scheduled CA, all patients received an additional evaluation with CTA. Included in the meta-analysis with the above-mentioned studies are 117 symptomatic patients with intermediate probability of CAD (10% - 90% probability), resulting in a pooled sensitivity of 96.1% (95%CI: 94.0%-98.3%) and pooled specificity of 81.5% (95%CI: 73.0% - 89.9%).
Summary of Findings
CTA is almost as good as CA in detecting true positives but poorer in the rate of false positives. The main value of CTA may be in ruling out significant CAD.
Increased prevalence of CAD decreases study specificity, whereas specificity is increased in the presence of increased arterial calcification even in lower prevalence studies.
Positive CT angiograms may require additional tests such as stress tests or the more invasive CA, partly to identify false positives.
Radiation exposure is an important safety concern that needs to be considered, particularly the cumulative exposures from repeat CTAs.
PMCID: PMC3377576  PMID: 23074388
5.  Carotid intima-media thickness (CIMT) and carotid plaques in young Nepalese patients with angiographically documented coronary artery disease 
Background
Carotid intima-media thickness (CIMT) and carotid plaques are non-invasive surrogate markers of early evaluation of coronary artery disease (CAD) and sub clinical atherosclerosis. The objective of the study was to evaluate CIMT and carotid plaques in less than 45 years old Nepalese patients with angiographically proven CAD.
Methods
A total of 54 patients with angiographically documented CAD at less than 45 years of age were enrolled. CAD was confirmed by coronary angiography. Demographic profile was obtained. High resolution B-mode ultrasound was used to detect the CIMT and carotid plaques.
Results
The study population included 44 males and 10 females, with a mean ± SD age of 38.4±4.3 years (range, 25-44 years). Cardiovascular risks factors included smoking in 81%, Hypertension in 52%, diabetes in 19% and alcohol consumption in 78% of patients. Lipid profile (mean ± SD) was normal except for elevated triglyceride (TG) levels of 204±130.8 mg/dL. By angiography, 64.8% had single vessel disease, 26% had double vessel disease and 9.2% had triple vessel disease. Ultrasound detected either thickened CIMT or presence of plaques in 46 (85.2%) cases (group-A) and 8 (14.8%) had negative (normal) carotid study (group-B). Among the 46 patients with positive findings 63% had carotid plaques and 37% had thickened CIMT only. The majority (69%) of the carotid plaques were detected at the carotid bulbs. In total population, carotid plaque was detected in 53.7% of cases. There was no statistical significant difference of age, body mass index (BMI) and lipid level between group-A and group-B.
Conclusions
Increased CIMT and carotid plaques are detected in majority of the young Nepalese patients with angiographically documented CAD. The majority of carotid plaques are detected at the carotid bulbs. Routine carotid ultrasound study in young individuals with CAD risk factors appears worthwhile.
doi:10.3978/j.issn.2223-3652.2015.01.10
PMCID: PMC4329159  PMID: 25774343
Coronary artery disease (CAD); carotid intima-media thickness (CIMT); carotid plaques
6.  Unrecognized Non-Q-Wave Myocardial Infarction: Prevalence and Prognostic Significance in Patients with Suspected Coronary Disease 
PLoS Medicine  2009;6(4):e1000057.
Using delayed-enhancement cardiovascular magnetic resonance, Han Kim and colleagues show that in patients with suspected coronary disease the prevalence of unrecognized myocardial infarction without Q-waves is more than 3-fold higher than that with Q-waves and predicts subsequent mortality.
Background
Unrecognized myocardial infarction (UMI) is known to constitute a substantial portion of potentially lethal coronary heart disease. However, the diagnosis of UMI is based on the appearance of incidental Q-waves on 12-lead electrocardiography. Thus, the syndrome of non-Q-wave UMI has not been investigated. Delayed-enhancement cardiovascular magnetic resonance (DE-CMR) can identify MI, even when small, subendocardial, or without associated Q-waves. The aim of this study was to investigate the prevalence and prognosis associated with non-Q-wave UMI identified by DE-CMR.
Methods and Findings
We conducted a prospective study of 185 patients with suspected coronary disease and without history of clinical myocardial infarction who were scheduled for invasive coronary angiography. Q-wave UMI was determined by electrocardiography (Minnesota Code). Non-Q-wave UMI was identified by DE-CMR in the absence of electrocardiographic Q-waves. Patients were followed to determine the prognostic significance of non-Q-wave UMI. The primary endpoint was all-cause mortality. The prevalence of non-Q-wave UMI was 27% (50/185), compared with 8% (15/185) for Q-wave UMI. Patients with non-Q-wave UMI were older, were more likely to have diabetes, and had higher Framingham risk than those without MI, but were similar to those with Q-wave UMI. Infarct size in non-Q-wave UMI was modest (8%±7% of left ventricular mass), and left ventricular ejection fraction (LVEF) by cine-CMR was usually preserved (52%±18%). The prevalence of non-Q-wave UMI increased with the extent and severity of coronary disease on angiography (p<0.0001 for both). Over 2.2 y (interquartile range 1.8–2.7), 16 deaths occurred: 13 in non-Q-wave UMI patients (26%), one in Q-wave UMI (7%), and two in patients without MI (2%). Multivariable analysis including New York Heart Association class and LVEF demonstrated that non-Q-wave UMI was an independent predictor of all-cause mortality (hazard ratio [HR] 11.4, 95% confidence interval [CI] 2.5–51.1) and cardiac mortality (HR 17.4, 95% CI 2.2–137.4).
Conclusions
In patients with suspected coronary disease, the prevalence of non-Q-wave UMI is more than 3-fold higher than Q-wave UMI. The presence of non-Q-wave UMI predicts subsequent mortality, and is incremental to LVEF.
Trial Registration
Clinicaltrials.gov NCT00493168
Editors' Summary
Background
Coronary artery disease (CAD; also called coronary heart disease) is the leading cause of death among adults in developed countries. In the USA alone, it kills nearly half a million people every year. CAD is caused by narrowing of the coronary arteries, the blood vessels that supply the heart with oxygen and nutrients. With age, fatty deposits (atherosclerotic plaques) coat the walls of these arteries and restrict the heart's blood supply, which causes the characteristic symptoms of CAD—angina (chest pains that are usually relieved by rest) and shortness of breath. In addition, if a plaque breaks off the wall of a coronary artery, it can completely block that artery and kill part of the heart, which causes a potentially fatal heart attack (doctors call this a myocardial infarction or MI). Heart attacks are often characterized by long-lasting chest pain that is not relieved by rest. Risk factors for CAD include smoking, high blood pressure, high blood levels of cholesterol (a type of fat), and being overweight. Treatments for the condition include lifestyle changes (for example, losing weight), and medications that lower blood pressure and blood cholesterol. The narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Not everyone who has a heart attack has chest pain. In fact, some studies suggest that 40–60% of MIs have no obvious symptoms. It is important, however, that these “unrecognized” MIs (UMIs) are diagnosed because they have death rates similar to those of MIs with clinical symptoms and need to be treated in a similar way. Traditionally, UMIs have been diagnosed using an electrocardiogram (ECG). When the heart beats, it generates small electric waves that can be picked up by electrodes attached to the skin. The pattern of these waves (the ECG) provides information about the heart's health. Alterations in the ECG, leading to so-called Q-waves, indicate that a UMI has occurred some time previously. However, not all UMIs result in Q-waves. In this study, the researchers use a recently developed technique—delayed enhancement cardiovascular magnetic resonance (DE-CMR), which can detect heart damage even in patients whose Q-waves are absent—to measure the prevalence (the fraction of a population that has a disorder) of non-Q-wave UMI. The researchers also investigate whether non-Q-wave UMI increases the risk of death.
What Did the Researchers Do and Find?
The researchers used electrocardiography and DE-CMR to look for Q-wave and non-Q-wave UMI, respectively, in 185 patients with suspected CAD but no history of MI. They then followed the patients for 2 years to discover whether a diagnosis of non-Q-wave UMI predicted their likelihood of dying from any cause or from a heart problem. 27% of the patients had evidence of non-Q-wave UMI whereas only 8% had evidence of Q-wave UMI. Patients with non-Q-wave UMI tended to have only a small area of heart damage and, consistent with this limited damage, their hearts pumped near-normal volumes of blood. Examination of the patients' arteries with a technique called coronary angiography indicated that the patients with widespread and/or severe CAD had a higher prevalence of non-Q-wave UMI than those with limited CAD. Finally, patients with non-Q-wave UMI had an 11-fold higher risk of death from any cause and a 17-fold higher risk of death from a heart problem than patients without UMI.
What Do These Findings Mean?
These findings indicate that non-Q-wave UMI occurs more than 3-times as often in patients with suspected CAD than Q-wave UMI and that patients with non-Q-wave UMI have a much greater risk of dying than patients without MI. Thus, if all cases of UMI—both Q-wave and non-Q-wave UMI—could be identified, it might be possible to reduce the number of deaths among people with CAD. However, before any recommendations are made to include DE-CMR in the routine examination of people with suspected CAD to achieve this aim, additional studies must be undertaken to confirm that non-Q-wave UMI is a common feature of CAD and to test whether the early diagnosis of non-Q-wave UMI does extend the life expectancy of people with CAD.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000057.
This study is further discussed in a PLoS Medicine Perspective by Clara Chow
The MedlinePlus encyclopedia has pages on coronary heart disease, heart attacks, and electrocardiograms (in English and Spanish). MedlinePlus also provides links to further information on all aspects of heart disease (in English and Spanish)
Information is available from the US National Heart Lung and Blood Institute on coronary heart disease
The UK National Health Service Choices website also provides information about coronary heart disease (in several languages).
The Nobel Foundation provides an interactive electrocardiogram game
doi:10.1371/journal.pmed.1000057
PMCID: PMC2661255  PMID: 19381280
7.  Stress Echocardiography for the Diagnosis of Coronary Artery Disease 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas"> www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Pease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: an Evidence-Based Analysis
The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:
The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7
Objective
The objective of the analysis is to determine the diagnostic accuracy of stress echocardiography (ECHO) in the diagnosis of patients with suspected coronary artery disease (CAD) compared to coronary angiography (CA).
Stress Echocardiography
Stress ECHO is a non-invasive technology that images the heart using ultrasound. It is one of the most commonly employed imaging techniques for investigating a variety of cardiac abnormalities in both community and hospital settings. A complete ECHO exam includes M-mode, 2-dimensional (2-D) images and Doppler imaging.
In order to diagnosis CAD and assess whether myocardial ischemia is present, images obtained at rest are compared to those obtained during or immediately after stress. The most commonly used agents used to induce stress are exercise and pharmacological agents such as dobutamine and dipyridamole. The hallmark of stress-induced myocardial ischemia is worsening of wall motion abnormalities or the development of new wall motion abnormalities. A major challenge for stress ECHO is that the interpretation of wall motion contractility and function is subjective. This leads to inter-observer variability and reduced reproducibility. Further, it is estimated that approximately 30% of patients have sub-optimal stress ECHO exams. To overcome this limitation, contrast agents for LV opacification have been developed.
Although stress ECHO is a relatively easy to use technology that poses only a low risk of adverse events compared to other imaging technologies, it may potentially be overused and/or misused in CAD diagnosis. Several recent advances have been made focusing on quantitative methods for assessment, improved image quality and enhanced portability, however, evidence on the effectiveness and clinical utility of these enhancements is limited.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of stress ECHO for the diagnosis of patients with suspected CAD compared to the reference standard of CA?
What is the clinical utility1 of stress ECHO?
Literature Search
A literature search was performed on August 28, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until August 21, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any relevant studies not identified through the search.
Inclusion Criteria
Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, retrospective analyses
Minimum sample size of 20 enrolled patients
Comparison to CA (reference standard)
Definition of CAD specified as either ≥50%, ≥70% or ≥75% coronary artery stenosis on CA
Reporting accuracy data on individual patients (rather than accuracy data stratified by segments of the heart)
English
Human
Exclusion Criteria
Duplicate studies
Non-systematic reviews, case reports
Grey literature (e.g., conference abstracts)
Insufficient data for independent calculation of sensitivity and specificity
Use of ECHO for purposes other than diagnosis of CAD (e.g., arrhythmia, valvular disease, mitral stenosis, pre-operative risk of MI)
Transesophageal ECHO since its primary use is for non-CAD indications such as endocarditis, intracardiac thrombi, valvular disorders
Only resting ECHO performed
Outcomes of Interest
Accuracy outcomes (sensitivity, specificity, positive predictive value, negative predictive value)
Costs
Summary of Findings
Given the vast amount of published literature on stress ECHO, it was decided to focus on the studies contained in the comprehensive 2007 review by Heijenbrok-Kal et al. (1) as a basis for the MAS evidence-based analysis. In applying our inclusion and exclusion criteria, 105 observational studies containing information on 13,035 patients were included. Six studies examined stress ECHO with adenosine, 26 with dipyridamole and 77 with dobutamine, the latter being the most commonly used pharmacological stress ECHO agent in Ontario. A further 18 studies employed exercise as the stressor.2 The prevalence of CAD ranged from 19% to 94% with a mean estimated prevalence of 70%. Based on the results of these studies the following conclusions were made:
Based on the available evidence, stress ECHO is a useful imaging modality for the diagnosis of CAD in patients with suspected disease. The overall pooled sensitivity is 0.80 (95% CI: 0.77 – 0.82) and the pooled specificity is 0.84 (95% CI: 0.82 – 0.87) using CA as the reference standard. The AUC derived from the sROC curve is 0.895 and the DOR is 20.64.
For pharmacological stress, the pooled sensitivity is 0.79 (95% CI: 0.71 – 0.87) and the pooled specificity is 0.85 (95% CI: 0.83 – 0.88). When exercise is employed as the stress agent, the pooled sensitivity is 0.81 (95% CI: 0.76– 0.86) and the pooled specificity is 0.79 (95% CI: 0.71 – 0.87). Although pharmacological stress and exercise stress would be indicated for different patient populations based on ability to exercise there were no significant differences in sensitivity and specificity.
Based on clinical experts, diagnostic accuracy on stress ECHO depends on the patient population, the expertise of the interpreter and the quality of the image.
PMCID: PMC3377563  PMID: 23074412
8.  Evaluating the Quality of Research into a Single Prognostic Biomarker: A Systematic Review and Meta-analysis of 83 Studies of C-Reactive Protein in Stable Coronary Artery Disease 
PLoS Medicine  2010;7(6):e1000286.
In a systematic review and meta-analysis of 83 prognostic studies of C-reactive protein in coronary disease, Hemingway and colleagues find substantial biases, preventing them from drawing clear conclusions relating to the use of this marker in clinical practice.
Background
Systematic evaluations of the quality of research on a single prognostic biomarker are rare. We sought to evaluate the quality of prognostic research evidence for the association of C-reactive protein (CRP) with fatal and nonfatal events among patients with stable coronary disease.
Methods and Findings
We searched MEDLINE (1966 to 2009) and EMBASE (1980 to 2009) and selected prospective studies of patients with stable coronary disease, reporting a relative risk for the association of CRP with death and nonfatal cardiovascular events. We included 83 studies, reporting 61,684 patients and 6,485 outcome events. No study reported a prespecified statistical analysis protocol; only two studies reported the time elapsed (in months or years) between initial presentation of symptomatic coronary disease and inclusion in the study. Studies reported a median of seven items (of 17) from the REMARK reporting guidelines, with no evidence of change over time.
The pooled relative risk for the top versus bottom third of CRP distribution was 1.97 (95% confidence interval [CI] 1.78–2.17), with substantial heterogeneity (I2 = 79.5). Only 13 studies adjusted for conventional risk factors (age, sex, smoking, obesity, diabetes, and low-density lipoprotein [LDL] cholesterol) and these had a relative risk of 1.65 (95% CI 1.39–1.96), I2 = 33.7. Studies reported ten different ways of comparing CRP values, with weaker relative risks for those based on continuous measures. Adjusting for publication bias (for which there was strong evidence, Egger's p<0.001) using a validated method reduced the relative risk to 1.19 (95% CI 1.13–1.25). Only two studies reported a measure of discrimination (c-statistic). In 20 studies the detection rate for subsequent events could be calculated and was 31% for a 10% false positive rate, and the calculated pooled c-statistic was 0.61 (0.57–0.66).
Conclusion
Multiple types of reporting bias, and publication bias, make the magnitude of any independent association between CRP and prognosis among patients with stable coronary disease sufficiently uncertain that no clinical practice recommendations can be made. Publication of prespecified statistical analytic protocols and prospective registration of studies, among other measures, might help improve the quality of prognostic biomarker research.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Coronary artery disease is the leading cause of death among adults in developed countries. With age, fatty deposits called atherosclerotic plaques coat the walls of the arteries, the vessels that carry blood to the body's organs. Because they narrow the arteries, atherosclerotic plaques restrict blood flow. If plaques form in the arteries that feed the heart, the result is coronary artery disease, the symptoms of which include shortness of breath and chest pains (angina). If these symptoms only occur during exertion, the condition is called stable coronary artery disease. Coronary artery disease can cause potentially fatal heart attacks (myocardial infarctions). A heart attack occurs when a plaque ruptures and a blood clot completely blocks the artery, thereby killing part of the heart. Smoking, high blood pressure, high blood levels of cholesterol (a type of fat), diabetes, and being overweight are risk factors for coronary artery disease. Treatments for the condition include lifestyle changes and medications that lower blood pressure and blood cholesterol. Narrowed arteries can also be widened using a device called a stent or surgically bypassed.
Why Was This Study Done?
Clinicians can predict whether a patient with coronary artery disease is likely to have a heart attack by considering their risk factors. They then use this “prognosis” to help them manage the patient. To provide further help for clinicians, researchers are trying to identify prognostic biomarkers (molecules whose blood levels indicate how a disease might develop) for coronary artery disease. However, before a biomarker can be used clinically, it must be properly validated and there are concerns that there is insufficient high quality evidence to validate many biomarkers. In this systematic review and meta-analysis, the researchers ask whether the evidence for an association between blood levels of C-reactive protein (CRP, an inflammatory protein) and subsequent fatal and nonfatal events affecting the heart and circulation (cardiovascular events) among patients with stable coronary artery disease supports the routine measurement of CRP as recommended in clinical practice guidelines. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method for combining the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 83 studies that investigated the association between CRP levels measured in people with coronary artery disease and subsequent cardiovascular events. Their examination of these studies revealed numerous reporting and publication short-comings. For example, none of the studies reported a prespecified statistical analysis protocol, yet analyses should be prespecified to avoid the choice of analytical method biasing the study's results. Furthermore, on average, the studies only reported seven of the 17 recommended items in the REMARK reporting guidelines, which were designed to improve the reporting quality of tumor biomarker prognostic studies. The meta-analysis revealed that patients with a CRP level in the top third of the distribution were nearly twice as likely to have a cardiovascular event as patients with a CRP in the bottom third of the distribution (a relative risk of 1.97). However, the outcomes varied considerably between studies (heterogeneity) and there was strong evidence for publication bias—most published studies were small and smaller studies were more likely to report higher relative risks. Adjustment for publication bias reduced the relative risk associated with high CRP levels to 1.19. Finally, nearly all the studies failed to calculate whether CRP measurements discriminated between patients likely and unlikely to have a subsequent cardiovascular event.
What Do These Findings Mean?
These findings suggest that, because of multiple types of reporting and publication bias, the size of the association between CRP levels and prognosis among patients with stable coronary artery disease is extremely uncertain. They also suggest that CRP measurements are unlikely to add anything to the prognostic discrimination achieved by considering blood pressure and other standard clinical factors among this patient group. Thus, the researchers suggest, the recommendation that CRP measurements should be used in the management of patients with stable coronary artery disease ought to be removed from clinical practice guidelines. More generally, these findings increase concerns about the quality of research into prognostic biomarkers and highlight areas that need to be changed, the most fundamental of which is the need to preregister studies on prognostic biomarkers and their analytic protocols.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000286.
The MedlinePlus Encyclopedia has pages on coronary artery disease and C-reactive protein (in English and Spanish)
MedlinePlus provides links to other sources of information on heart disease
The American Heart Association provides information for patients and caregivers on all aspects of cardiovascular disease, including information on the role of C-reactive protein in heart disease
Information is available from the British Heart Foundation on heart disease and keeping the heart healthy
Wikipedia has pages on biomarkers and on C-reactive protein (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The EQUATOR network is a resource center for good reporting of health research studies
doi:10.1371/journal.pmed.1000286
PMCID: PMC2879408  PMID: 20532236
9.  Framingham cardiovascular risk in patients with obesity and periodontitis 
Background:
Obesity is a chronic inflammatory condition that has been associated to a risk factor for the development of periodontitis and cardiovascular disease; however, the relationship still needs to be clarified. The objective of this study was to evaluate the cardiovascular risk in obese patients with chronic periodontitis.
Materials and Methods:
A total of 87 obese patients were evaluated for anthropometric data (body mass index [BMI], waist circumference, body fat), systolic blood pressure (SBP) and diastolic blood pressure (DBP), cholesterol, high-density lipoprotein (HDL) and low-density lipoprotein (LDL), triglycerides, glycemia and periodontal parameters (visible plaque index (VPI), gingival bleeding index (GBI), bleeding on probing (BOP), periodontal probing depth (PPD) and clinical attachment level (CAL)).
Results:
Patients were divided into two groups according to the periodontal characteristics found: Group O-PD: Obese patients with chronic periodontitis (n = 45), 22 men and 23 women; and Group O-sPD: Obese patients without chronic periodontitis (n = 42), 17 men and 25 women. Patients had a BMI mean of 35.2 (±5.1) kg/m2 . Group O-PD showed a similarity between the genders regarding age, SBP, DBP, cholesterol, HDL, GBI, VPI, PPD ≥4 mm and CAL ≥4 mm. O-PD women showed greater glycemia level and smoking occurrence, but O-PD men presented a 13% - risk over of developing coronary artery disease in 10 years than O-PD women, 9% - risk over than O-sPD men and 15% - risk over than O-sPD women, by the Framingham Score.
Conclusions:
It was concluded that obesity and periodontal disease are cardiovascular risk factors and that the two associated inflammatory conditions potentially increases the risk for heart diseases.
doi:10.4103/0972-124X.128193
PMCID: PMC3988634  PMID: 24744538
Cardiovascular disease; obesity; periodontal disease
10.  Implication of plasma intermedin levels in patients who underwent first-time diagnostic coronary angiography: a single centre, cross-sectional study 
Background
Intermedin (IMD) is involved in the prevention of atherosclerotic plaque progression, possessing cardioprotective effects from hypertrophy, fibrosis and ischemia-reperfusion injury. Elevated plasma IMD levels have been demonstrated in patients with acute coronary syndromes. No human study has examined the role of IMD in stable patients who underwent diagnostic coronary angiography with suspicion of coronary artery disease (CAD). Thus we investigated the role of IMD as a biomarker to discriminate patients with CAD and predict those with severe disease who require early and intensive therapeutic intervention before presenting with acute coronary syndrome.
Methods
Eligible two hundred and thirty-eight consecutive patients (123 males, mean age 58.4 ± 10.0 years) who underwent first-time diagnostic coronary angiography were included in this study. Plasma concentrations of IMD were measured from arterial blood samples by the enzyme-linked immunosorbent assay. Patients were divided into three groups according to the presence and degree of CAD, consisting of 48 patients with normal coronary anatomy (Group 1), 111 patients with < 50% coronary stenosis (Group 2), and 79 patients with ≥ 50% stenosis in at least one of the major coronary arteries (group 3). The severity and extent of CAD was evaluated by calculations of the vessel, Gensini, and SYNTAX scores.
Results
Circulating plasma IMD levels in patients with CAD were significantly higher than those in patients without CAD (157.7 ± 9.6, 134.8 ± 11.9, and 117.6 ± 7.9 pg/mL in groups 3, 2 and 1 respectively; p < 0.001). Besides, plasma IMD levels were correlated with Gensini and SYNTAX scores (rs = 0.742, and rs = 0.296, respectively; p < 0.05). The presence of ≥50% coronary artery stenosis could be predicted if a cut-off value of 147.7 pg/mL for plasma IMD was used with 88.6% sensitivity and 88.7% specificity. Moreover, a plasma IMD level of <126.6 pg/mL could discriminate a patient with normal coronary arteries from patients with angiographically proven CAD with a sensitivity and specificity of 84.7%, and 83.3% respectively.
Conclusions
We demonstrated that IMD might be used as a biomarker to predict CAD and its severity in patients who underwent first time diagnostic coronary angiography.
doi:10.1186/1471-2261-14-182
PMCID: PMC4271361  PMID: 25495100
Intermedin; Coronary artery disease; Diagnostic coronary angiography
11.  Burden of Hospital Admission and Repeat Angiography in Angina Pectoris Patients with and without Coronary Artery Disease: A Registry-Based Cohort Study 
PLoS ONE  2014;9(4):e93170.
Aims
To evaluate risk of hospitalization due to cardiovascular disease (CVD) and repeat coronary angiography (CAG) in stable angina pectoris (SAP) with no obstructive coronary artery disease (CAD) versus obstructive CAD, and asymptomatic reference individuals.
Methods and Results
We followed 11,223 patients with no prior CVD having a first-time CAG in 1998–2009 due to SAP symptoms and 5,695 asymptomatic reference individuals from the Copenhagen City Heart Study through registry linkage for 7.8 years (median). In recurrent event survival analysis, patients with SAP had 3–4-fold higher risk of hospitalization for CVD irrespective of CAG findings and cardiovascular comorbidity. Multivariable adjusted hazard ratios(95%CI) for patients with angiographically normal coronary arteries was 3.0(2.5–3.5), for angiographically diffuse non-obstructive CAD 3.9(3.3–4.6) and for 1–3-vessel disease 3.6–4.1(range)(all P<0.001). Mean accumulated hospitalization time was 3.5(3.0–4.0)(days/10 years follow-up) in reference individuals and 4.5(3.8–5.2)/7.0(5.4–8.6)/6.7(5.2–8.1)/6.1(5.2–7.4)/8.6(6.6–10.7) in patients with angiographically normal coronary arteries/angiographically diffuse non-obstructive CAD/1-, 2-, and 3-vessel disease, respectively (all P<0.05, age-adjusted). SAP symptoms predicted repeat CAG with multivariable adjusted hazard ratios for patients with angiographically normal coronary arteries being 2.3(1.9–2.9), for angiographically diffuse non-obstructive CAD 5.5(4.4–6.8) and for obstructive CAD 6.6–9.4(range)(all P<0.001).
Conclusions
Patients with SAP symptoms and angiographically normal coronary arteries or angiographically diffuse non-obstructive CAD suffer from considerably greater CVD burdens in terms of hospitalization for CVD and repeat CAG compared with asymptomatic reference individuals even after adjustment for cardiac risk factors and exclusion of cardiovascular comorbidity as cause. Contrary to common perception, excluding obstructive CAD by CAG in such patients does not ensure a benign cardiovascular prognosis.
doi:10.1371/journal.pone.0093170
PMCID: PMC3976412  PMID: 24705387
12.  Serum protein profiles predict coronary artery disease in symptomatic patients referred for coronary angiography 
BMC Medicine  2012;10:157.
Background
More than a million diagnostic cardiac catheterizations are performed annually in the US for evaluation of coronary artery anatomy and the presence of atherosclerosis. Nearly half of these patients have no significant coronary lesions or do not require mechanical or surgical revascularization. Consequently, the ability to rule out clinically significant coronary artery disease (CAD) using low cost, low risk tests of serum biomarkers in even a small percentage of patients with normal coronary arteries could be highly beneficial.
Methods
Serum from 359 symptomatic subjects referred for catheterization was interrogated for proteins involved in atherogenesis, atherosclerosis, and plaque vulnerability. Coronary angiography classified 150 patients without flow-limiting CAD who did not require percutaneous intervention (PCI) while 209 required coronary revascularization (stents, angioplasty, or coronary artery bypass graft surgery). Continuous variables were compared across the two patient groups for each analyte including calculation of false discovery rate (FDR ≤ 1%) and Q value (P value for statistical significance adjusted to ≤ 0.01).
Results
Significant differences were detected in circulating proteins from patients requiring revascularization including increased apolipoprotein B100 (APO-B100), C-reactive protein (CRP), fibrinogen, vascular cell adhesion molecule 1 (VCAM-1), myeloperoxidase (MPO), resistin, osteopontin, interleukin (IL)-1β, IL-6, IL-10 and N-terminal fragment protein precursor brain natriuretic peptide (NT-pBNP) and decreased apolipoprotein A1 (APO-A1). Biomarker classification signatures comprising up to 5 analytes were identified using a tunable scoring function trained against 239 samples and validated with 120 additional samples. A total of 14 overlapping signatures classified patients without significant coronary disease (38% to 59% specificity) while maintaining 95% sensitivity for patients requiring revascularization. Osteopontin (14 times) and resistin (10 times) were most frequently represented among these diagnostic signatures. The most efficacious protein signature in validation studies comprised osteopontin (OPN), resistin, matrix metalloproteinase 7 (MMP7) and interferon γ (IFNγ) as a four-marker panel while the addition of either CRP or adiponectin (ACRP-30) yielded comparable results in five protein signatures.
Conclusions
Proteins in the serum of CAD patients predominantly reflected (1) a positive acute phase, inflammatory response and (2) alterations in lipid metabolism, transport, peroxidation and accumulation. There were surprisingly few indicators of growth factor activation or extracellular matrix remodeling in the serum of CAD patients except for elevated OPN. These data suggest that many symptomatic patients without significant CAD could be identified by a targeted multiplex serum protein test without cardiac catheterization thereby eliminating exposure to ionizing radiation and decreasing the economic burden of angiographic testing for these patients.
doi:10.1186/1741-7015-10-157
PMCID: PMC3566965  PMID: 23216991
atherosclerosis; biomarkers; cardiac catheterization; coronary angiography; coronary stenosis; multiplex proteomics
13.  Underweight, Markers of Cachexia, and Mortality in Acute Myocardial Infarction: A Prospective Cohort Study of Elderly Medicare Beneficiaries 
PLoS Medicine  2016;13(4):e1001998.
Background
Underweight patients are at higher risk of death after acute myocardial infarction (AMI) than normal weight patients; however, it is unclear whether this relationship is explained by confounding due to cachexia or other factors associated with low body mass index (BMI). This study aimed to answer two questions: (1) does comprehensive risk adjustment for comorbid illness and frailty measures explain the higher mortality after AMI in underweight patients, and (2) is the relationship between underweight and mortality also observed in patients with AMI who are otherwise without significant chronic illness and are presumably free of cachexia?
Methods and Findings
We analyzed data from the Cooperative Cardiovascular Project, a cohort-based study of Medicare beneficiaries hospitalized for AMI between January 1994 and February 1996 with 17 y of follow-up and detailed clinical information to compare short- and long-term mortality in underweight and normal weight patients (n = 57,574). We used Cox proportional hazards regression to investigate the association of low BMI with 30-d, 1-y, 5-y, and 17-y mortality after AMI while adjusting for patient comorbidities, frailty measures, and laboratory markers of nutritional status. We also repeated the analyses in a subset of patients without significant comorbidity or frailty.
Of the 57,574 patients with AMI included in this cohort, 5,678 (9.8%) were underweight and 51,896 (90.2%) were normal weight at baseline. Underweight patients were older, on average, than normal weight patients and had a higher prevalence of most comorbidities and measures of frailty. Crude mortality was significantly higher for underweight patients than normal weight patients at 30 d (25.2% versus 16.4%, p < 0.001), 1 y (51.3% versus 33.8%, p < 0.001), 5 y (79.2% versus 59.4%, p < 0.001), and 17 y (98.3% versus 94.0%, p < 0.001). After adjustment, underweight patients had a 13% higher risk of 30-d death and a 26% higher risk of 17-y death than normal weight patients (30-d hazard ratio [HR] 1.13, 95% CI 1.07–1.20; 17-y HR 1.26, 95% CI 1.23–1.30). Survival curves for underweight and normal weight patients separated early and remained separate over 17 y, suggesting that underweight patients remained at a significant survival disadvantage over time. Similar findings were observed among the subset of patients without comorbidity at baseline. Underweight patients without comorbidity had a 30-d adjusted mortality similar to that of normal weight patients but a 21% higher risk of death over the long term (30-d HR 1.08, 95% CI 0.93–1.26; 17-y HR 1.21, 95% CI 1.14–1.29). The adverse effects of low BMI were greatest in patients with very low BMIs. The major limitation of this study was the use of surrogate markers of frailty and comorbid conditions to identify patients at highest risk for cachexia rather than clear diagnostic criteria for cachexia.
Conclusions
Underweight BMI is an important risk factor for mortality after AMI, independent of confounding by comorbidities, frailty measures, and laboratory markers of nutritional status. Strategies to promote weight gain in underweight patients after AMI are worthy of testing.
In this prospective cohort study of elderly medicare beneficiaries, Harlan Krumholz and colleagues investigate the association between underweight and mortality after acute myocardial infarction independent of cachexia and frailty.
Editors' Summary
Background
A heart attack, or acute myocardial infarction (AMI), is a potentially fatal medical emergency that occurs when part of the heart muscle dies because the blood supply to the heart becomes blocked, usually by a blood clot. Every year in the US alone, more than three-quarters of a million people have a heart attack—more than one person every minute. Heart attacks are usually caused by coronary artery disease. With age, fatty deposits (atherosclerotic plaque) coat the walls of arteries, the vessels that supply the organs of the body with oxygen and nutrients. Coronary artery disease develops when plaques form in the arteries that supply the heart. A heart attack occurs when a blood clot forms in the narrowed vessel or when a plaque ruptures and triggers clot formation. Symptoms of a heart attack include chest pain, shortness of breath, and feeling lightheaded. Treatments for AMI include dissolving the blood clot with drugs and surgically opening up or bypassing the blocked artery.
Why Was This Study Done?
Underweight people are at a higher risk of death after AMI than normal weight people, but is being underweight a direct risk factor for death after AMI? “Confounding” by cachexia—unintentional weight loss, muscle wasting, and fatigue that occur in the setting of chronic disease—could explain excess mortality (death) among underweight patients. That is, people who are underweight may have a higher risk of death post-AMI than normal weight people because they have another underlying disease that has caused them to lose weight. If the relationship between being underweight and post-AMI mortality is largely explained by a comorbid (coexisting) illness, managing this underlying condition may improve outcomes, whereas if being underweight is an independent risk factor for death after AMI, promoting weight gain may improve outcomes. In this prospective cohort study, the researchers investigate whether comprehensive risk adjustment for comorbid illness and frailty measures explains the higher mortality after AMI in underweight patients, and they ask whether the relationship between being underweight and mortality is also observed post-AMI in patients who have no other significant chronic illness.
What Did the Researchers Do and Find?
The researchers used data from the Cooperative Cardiovascular Project, a US quality improvement initiative in which a cohort (group) of Medicare beneficiaries hospitalized for AMI were followed for many years (Medicare is a government-run program that funds healthcare for people aged ≥65 years in the US). Specifically, they analyzed short- and long-term mortality among 57,574 underweight and normal weight patients (individuals with a body mass index [BMI] of <18.5 kg/m2 and 18.5–24.9 kg/m2, respectively; BMI is an indicator of body fat calculated by dividing a person’s weight in kilograms by their height in meters squared). Crude mortality (deaths from all causes without adjustment for other factors likely to affect the risk of death) was higher among underweight patients than among normal weight patients at 30 days and 1, 5, and 17 years after AMI. After adjustment for comorbidities that cause cachexia (for example, cancer and chronic liver disease), variables reflecting frailty (such as mobility), and two laboratory measures of nutritional status, underweight patients had a 13% higher risk of death at 30 days and a 26% higher risk of death over 17 years than normal weight patients. Notably, among patients without comorbidity, underweight patients had a 21% higher risk of death over 17 years than normal weight patients.
What Do These Findings Mean?
These findings suggest that, although adjustment for markers of cachexia attenuated some of the excess risk of death among underweight patients compared to normal weight patients, being underweight is an important independent risk factor for death after AMI. Moreover, they suggest that underweight patients have a survival disadvantage compared with normal weight patients for many years after AMI. Because the researchers had no information on whether patients had recently lost weight (a more direct indicator of cachexia), they relied on markers of frailty and nutritional status and the presence of comorbidities to identify the patients at highest risk of cachexia, which may limit the accuracy of these findings. Importantly, however, these findings highlight the need for further research on underweight patients who have coronary artery disease and suggest that it may be worth testing strategies to promote weight gain in underweight patients after AMI as a way to reduce the excess mortality in this group of patients compared to normal weight patients.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001998.
The US Centers for Disease Control and Prevention has detailed information on coronary artery disease and myocardial infarction
The NIH Senior Health website includes information on heart attack
The UK National Health Service Choices website provides information about all aspects of coronary artery disease and heart attack (including personal stories) and information about being underweight
The American Heart Association provides information on all aspects of cardiovascular disease and tips on keeping the heart healthy; its website includes personal stories about heart attack
The US National Heart, Lung, and Blood Institute also provides information on coronary artery disease and heart attack (in English and Spanish)
MedlinePlus provides links to other sources of information on heart attack and coronary artery disease (in English and Spanish)
Wikipedia has a page on cachexia (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
doi:10.1371/journal.pmed.1001998
PMCID: PMC4836735  PMID: 27093615
14.  Epicardial Adipose Tissue Thickness and Its Association With the Presence and Severity of Coronary Artery Disease in Clinical Setting: A Cross-Sectional Observational Study 
Background
Obesity is an important risk factor for atherosclerotic cardiovascular disease (ASCVD). Estimation of visceral adipose tissue is important and several methods are available as its surrogate. Although correlation of epicardial adipose tissue (EAT) with visceral adipose tissue as estimated by magnetic resonance imaging (MRI) and/or CT is excellent, it is costlier and cumbersome. EAT can be accurately measured by two-dimensional (2D) echocardiography. It tends to be higher in patients with acute coronary syndrome than in subjects without coronary artery disease (CAD) and in those with stable angina. It also carries advantage as index of high cardiometabolic risk as it is a direct measure of visceral fat rather than anthropometric measurements. The present study evaluated the relationship of EAT to the presence and severity of CAD in clinical setting.
Methods
In this prospective, single-center study conducted in the Department of Cardiology, LPS Institute of Cardiology, Kanpur, India, 549 consecutive patients with acute coronary syndrome or chronic stable angina were enrolled. Sensitivity, specificity, and receiver operating characteristic (ROC) curve were estimated to find cut-off value of EAT thickness for diagnosing CAD using coronary angiographic findings as gold standard.
Results
Patients were diagnosed as CAD group (n = 464, 60.30 ± 8.36 years) and non-CAD group (n = 85, 54.42 ± 11.93 years) after assessing coronary angiograms. The EAT was measured at end-systole from the PLAX views of three cardiac cycles on the free wall of the right ventricle. Lesion was significant if > 50% in left main and > 70% in other coronary arteries. The mean EAT thickness in CAD group was 5.10 ± 1.06 and in non-CAD group was 4.36 ± 1.01 which was significant (P = 0.003). Significant correlation was demonstrated between EAT thickness and presence of CAD (P < 0.003). Higher EAT was associated with severe CAD and presence of multivessel disease. By ROC analysis, EAT > 4.65 mm predicated the presence of significant coronary stenosis by 71.6% sensitivity and 73.1% specificity.
Conclusion
EAT thickness measured using transthoracic echocardiography (TTE) significantly correlates with the presence and severity of CAD. It is sensitive, easily available, and cost-effective and assists in the risk stratification and may be an additional marker on classical risk factors for CAD.
doi:10.14740/jocmr2468w
PMCID: PMC4817582  PMID: 27081428
Acute coronary syndrome; Chronic stable angina; Coronary artery stenosis; Epicardial fat thickness; Echocardiography; ROC curve; TTE
15.  Stenting for Peripheral Artery Disease of the Lower Extremities 
Executive Summary
Background
Objective
In January 2010, the Medical Advisory Secretariat received an application from University Health Network to provide an evidentiary platform on stenting as a treatment management for peripheral artery disease. The purpose of this health technology assessment is to examine the effectiveness of primary stenting as a treatment management for peripheral artery disease of the lower extremities.
Clinical Need: Condition and Target Population
Peripheral artery disease (PAD) is a progressive disease occurring as a result of plaque accumulation (atherosclerosis) in the arterial system that carries blood to the extremities (arms and legs) as well as vital organs. The vessels that are most affected by PAD are the arteries of the lower extremities, the aorta, the visceral arterial branches, the carotid arteries and the arteries of the upper limbs. In the lower extremities, PAD affects three major arterial segments i) aortic-iliac, ii) femoro-popliteal (FP) and iii) infra-popliteal (primarily tibial) arteries. The disease is commonly classified clinically as asymptomatic claudication, rest pain and critical ischemia.
Although the prevalence of PAD in Canada is not known, it is estimated that 800,000 Canadians have PAD. The 2007 Trans Atlantic Intersociety Consensus (TASC) II Working Group for the Management of Peripheral Disease estimated that the prevalence of PAD in Europe and North America to be 27 million, of whom 88,000 are hospitalizations involving lower extremities. A higher prevalence of PAD among elderly individuals has been reported to range from 12% to 29%. The National Health and Nutrition Examination Survey (NHANES) estimated that the prevalence of PAD is 14.5% among individuals 70 years of age and over.
Modifiable and non-modifiable risk factors associated with PAD include advanced age, male gender, family history, smoking, diabetes, hypertension and hyperlipidemia. PAD is a strong predictor of myocardial infarction (MI), stroke and cardiovascular death. Annually, approximately 10% of ischemic cardiovascular and cerebrovascular events can be attributed to the progression of PAD. Compared with patients without PAD, the 10-year risk of all-cause mortality is 3-fold higher in patients with PAD with 4-5 times greater risk of dying from cardiovascular event. The risk of coronary heart disease is 6 times greater and increases 15-fold in patients with advanced or severe PAD. Among subjects with diabetes, the risk of PAD is often severe and associated with extensive arterial calcification. In these patients the risk of PAD increases two to four fold. The results of the Canadian public survey of knowledge of PAD demonstrated that Canadians are unaware of the morbidity and mortality associated with PAD. Despite its prevalence and cardiovascular risk implications, only 25% of PAD patients are undergoing treatment.
The diagnosis of PAD is difficult as most patients remain asymptomatic for many years. Symptoms do not present until there is at least 50% narrowing of an artery. In the general population, only 10% of persons with PAD have classic symptoms of claudication, 40% do not complain of leg pain, while the remaining 50% have a variety of leg symptoms different from classic claudication. The severity of symptoms depends on the degree of stenosis. The need to intervene is more urgent in patients with limb threatening ischemia as manifested by night pain, rest pain, ischemic ulcers or gangrene. Without successful revascularization those with critical ischemia have a limb loss (amputation) rate of 80-90% in one year.
Diagnosis of PAD is generally non-invasive and can be performed in the physician offices or on an outpatient basis in a hospital. Most common diagnostic procedure include: 1) Ankle Brachial Index (ABI), a ratio of the blood pressure readings between the highest ankle pressure and the highest brachial (arm) pressure; and 2) Doppler ultrasonography, a diagnostic imaging procedure that uses a combination of ultrasound and wave form recordings to evaluate arterial flow in blood vessels. The value of the ABI can provide an assessment of the severity of the disease. Other non invasive imaging techniques include: Computed Tomography (CT) and Magnetic Resonance Angiography (MRA). Definitive diagnosis of PAD can be made by an invasive catheter based angiography procedure which shows the roadmap of the arteries, depicting the exact location and length of the stenosis / occlusion. Angiography is the standard method against which all other imaging procedures are compared for accuracy.
More than 70% of the patients diagnosed with PAD remain stable or improve with conservative management of pharmacologic agents and life style modifications. Significant PAD symptoms are well known to negatively influence an individual quality of life. For those who do not improve, revascularization methods either invasive or non-invasive can be used to restore peripheral circulation.
Technology Under Review
A Stent is a wire mesh “scaffold” that is permanently implanted in the artery to keep the artery open and can be combined with angioplasty to treat PAD. There are two types of stents: i) balloon-expandable and ii) self expandable stents and are available in varying length. The former uses an angioplasty balloon to expand and set the stent within the arterial segment. Recently, drug-eluting stents have been developed and these types of stents release small amounts of medication intended to reduce neointimal hyperplasia, which can cause re-stenosis at the stent site. Endovascular stenting avoids the problem of early elastic recoil, residual stenosis and flow limiting dissection after balloon angioplasty.
Research Questions
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting more effective than percutaneous transluminal angioplasty (PTA) in improving patency?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting provide immediate success compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), is primary stenting associated with less complications compared to PTA?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion), does primary stenting compared to PTA reduce the rate of re-intervention?
In individuals with PAD of the lower extremities (superficial femoral artery, infra-popliteal, crural and iliac artery stenosis or occlusion) is primary stenting more effective than PTA in improving clinical and hemodynamic success?
Are drug eluting stents more effective than bare stents in improving patency, reducing rates of re-interventions or complications?
Research Methods
Literature Search
A literature search was performed on February 2, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA). Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language full-reports from 1950 to January Week 3, 2010
Comparative randomized controlled trials (RCTs), systematic reviews and meta-analyses of RCTs
Proven diagnosis of PAD of the lower extremities in all patients.
Adult patients at least 18 years of age.
Stent as at least one treatment arm.
Patency, re-stenosis, re-intervention, technical success, hemodynamic (ABI) and clinical improvement and complications as at least an outcome.
Exclusion Criteria
Non-randomized studies
Observational studies (cohort or retrospective studies) and case report
Feasibility studies
Studies that have evaluated stent but not as a primary intervention
Outcomes of Interest
The primary outcome measure was patency. Secondary measures included technical success, re-intervention, complications, hemodynamic (ankle brachial pressure index, treadmill walking distance) and clinical success or improvement according to Rutherford scale. It was anticipated, a priori, that there would be substantial differences among trials regarding the method of examination and definitions of patency or re-stenosis. Where studies reported only re-stenosis rates, patency rates were calculated as 1 minus re-stenosis rates.
Statistical Analysis
Odds ratios (for binary outcomes) or mean difference (for continuous outcomes) with 95% confidence intervals (CI) were calculated for each endpoint. An intention to treat principle (ITT) was used, with the total number of patients randomized to each study arm as the denominator for each proportion. Sensitivity analysis was performed using per protocol approach. A pooled odds ratio (POR) or mean difference for each endpoint was then calculated for all trials reporting that endpoint using a fixed effects model. PORs were calculated for comparisons of primary stenting versus PTA or other alternative procedures. Level of significance was set at alpha=0.05. Homogeneity was assessed using the chi-square test, I2 and by visual inspection of forest plots. If heterogeneity was encountered within groups (P < 0.10), a random effects model was used. All statistical analyses were performed using RevMan 5. Where sufficient data were available, these analyses were repeated within subgroups of patients defined by time of outcome assessment to evaluate sustainability of treatment benefit. Results were pooled based on the diseased artery and stent type.
Summary of Findings
Balloon-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, there is no significant difference in patency between primary stenting using balloon-expandable bare metal stents and PTA at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 1.26 (0.74, 2.13); 12 months 0.95 (0.66, 1.38); and 24 months 0.72 (0.34. 1.55).
There is no significant difference in clinical improvement, re-interventions, peri and post operative complications, mortality and amputations between primary stenting using balloon-expandable bare stents and PTA in patients with superficial femoral artery. The pooled OR and their corresponding 95% CI are clinical improvement 0.85 (0.50, 1.42); ankle brachial index 0.01 (-0.02, 0.04) re-intervention 0.83 (0.26, 2.65); complications 0.73 (0.43, 1.22); all cause mortality 1.08 (0.59, 1.97) and amputation rates 0.41 (0.14, 1.18).
Self-expandable stents vs PTA in superficial femoral artery disease
Based on a moderate quality of evidence, primary stenting using self-expandable bare metal stents is associated with significant improvement in patency at 6, 12 and 24 months in patients with superficial femoral artery disease. The pooled OR for patency and their corresponding 95% CI are: 6 months 2.35 (1.06, 5.23); 12 months 1.54 (1.01, 2.35); and 24 months 2.18 (1.00. 4.78). However, the benefit of primary stenting is not observed for clinical improvement, re-interventions, peri and post operative complications, mortality and amputation in patients with superficial femoral artery disease. The pooled OR and their corresponding 95% CI are clinical improvement 0.61 (0.37, 1.01); ankle brachial index 0.01 (-0.06, 0.08) re-intervention 0.60 (0.36, 1.02); complications 1.60 (0.53, 4.85); all cause mortality 3.84 (0.74, 19.22) and amputation rates 1.96 (0.20, 18.86).
Balloon expandable stents vs PTA in iliac artery occlusive disease
Based on moderate quality of evidence, despite immediate technical success, 12.23 (7.17, 20.88), primary stenting is not associated with significant improvement in patency, clinical status, treadmill walking distance and reduction in re-intervention, complications, cardiovascular events, all cause mortality, QoL and amputation rates in patients with intermittent claudication caused by iliac artery occlusive disease. The pooled OR and their corresponding 95% CI are: patency 1.03 (0.56, 1.87); clinical improvement 1.08 (0.60, 1.94); walking distance 3.00 (12.96, 18.96); re-intervention 1.16 (0.71, 1.90); complications 0.56 (0.20, 1.53); all cause mortality 0.89 (0.47, 1.71); QoL 0.40 (-4.42, 5.52); cardiovascular event 1.16 (0.56, 2.40) and amputation rates 0.37 (0.11, 1.23). To date no RCTs are available evaluating self-expandable stents in the common or external iliac artery stenosis or occlusion.
Drug-eluting stent vs balloon-expandable bare metal stents in crural arteries
Based on a very low quality of evidence, at 6 months of follow-up, sirolimus drug-eluting stents are associated with a reduction in target vessel revascularization and re-stenosis rates in patients with atherosclerotic lesions of crural (tibial) arteries compared with balloon-expandable bare metal stent. The OR and their corresponding 95% CI are: re-stenosis 0.09 (0.03, 0.28) and TVR 0.15 (0.05, 0.47) in patients with atherosclerotic lesions of the crural arteries at 6 months follow-up. Both types of stents offer similar immediate success. Limitations of this study include: short follow-up period, small sample and no assessment of mortality as an outcome. Further research is needed to confirm its effect and safety.
PMCID: PMC3377569  PMID: 23074395
16.  Epicardial Adipose Tissue Thickness Correlates with the Presence and Severity of Angiographic Coronary Artery Disease in Stable Patients with Chest Pain 
PLoS ONE  2014;9(10):e110005.
Objective
Epicardial adipose tissue (EAT) is suggested to correlate with metabolic risk factors and to promote plaque development in the coronary arteries. We sought to determine whether EAT thickness was associated or not with the presence and extent of angiographic coronary artery disease (CAD).
Methods
We measured epicardial fat thickness by computed tomography and assessed the presence and extent of CAD by coronary angiography in participants from the prospective EVASCAN study. The association of EAT thickness with cardiovascular risk factors, coronary artery calcification scoring and angiographic CAD was assessed using multivariate regression analysis.
Results
Of 970 patients (age 60.9 years, 71% male), 75% (n = 731) had CAD. Patients with angiographic CAD had thicker EAT on the left ventricle lateral wall when compared with patients without CAD (2.74±2.4 mm vs. 2.08±2.1 mm; p = 0.0001). The adjusted odds ratio (OR) for a patient with a LVLW EAT value ≥2.8 mm to have CAD was OR = 1.46 [1.03–2.08], p = 0.0326 after adjusting for risk factors. EAT also correlated with the number of diseased vessels (p = 0.0001 for trend). By receiver operating characteristic curve analysis, an EAT value ≥2.8 mm best predicted the presence of>50% diameter coronary artery stenosis, with a sensitivity and specificity of 46.1% and 66.5% respectively (AUC:0.58). Coronary artery calcium scoring had an AUC of 0.76.
Conclusion
Although left ventricle lateral wall EAT thickness correlated with the presence and extent of angiographic CAD, it has a low performance for the diagnosis of CAD.
doi:10.1371/journal.pone.0110005
PMCID: PMC4204866  PMID: 25335187
17.  Assessment of the effect of periodontal treatment in patients with coronary artery disease : A pilot survey 
Background:
Periodontitis is a chronic inflammatory condition believed to cause a low but long lasting systemic inflammatory reaction which in turn contributes to the development of atherosclerosis. Recent data suggests that around 40% cases of coronary artery disease remain unaccounted despite the identification of the classical risk factors.
Objectives:
To evaluate the efficacy of non surgical periodontal therapy on the levels of serum inflammatory markers in subjects with chronic periodontitis and known coronary artery disease.
Materials and Methods:
Twenty subjects with known coronary artery disease (CAD) were recruited from the Department of Cardiology, CSM Medical University, Lucknow, India, for this study. Periodontal disease was measured through the clinical parameters bleeding on probing (BOP) and probing depth (PD). All subjects received non surgical periodontal therapy that included oral hygiene instructions and meticulous scaling and root planing. Systemic levels of inflammatory markers such as high-sensitivity C reactive proteins (hsCRP), tumor necrosis factor-α (TNF-α), and white blood cell (WBC) counts were measured prior to and 1 month after periodontal therapy.
Results:
Subjects experienced significant reductions in bleeding on probing (BOP) and probing depth (PD), indicating improvement in overall periodontal health. In all subjects, high-sensitivity C reactive proteins (hsCRP), and WBC counts were reduced significantly,; however, tumor necrosis factor-α (TNF-α) levels showed no statistically significant reduction.
Conclusion:
In this study, periodontal treatment resulted in a significant decrease in bleeding on probing (BOP) and probing depth (PD), and this treatment lowered the serum inflammatory markers (hsCRP and WBC counts) in patients with coronary artery disease. This may result in a decreased risk for coronary artery disease in the periodontally treated patients.
doi:10.4103/0975-3583.95366
PMCID: PMC3354455  PMID: 22629030
Coronary artery disease; high-sensitivity C-reactive protein; periodontitis; tumor necrosis factor-α
18.  Impact of Prediabetic Status on Coronary Atherosclerosis 
Diabetes Care  2013;36(3):729-733.
OBJECTIVE
To determine if prediabetes is associated with atherosclerosis of coronary arteries, we evaluated the degree of coronary atherosclerosis in nondiabetic, prediabetic, and diabetic patients by using coronary angioscopy to identify plaque vulnerability based on yellow color intensity.
RESEARCH DESIGN AND METHODS
Sixty-seven patients with coronary artery disease (CAD) underwent angioscopic observation of multiple main-trunk coronary arteries. According to the American Diabetes Association guidelines, patients were divided into nondiabetic (n = 16), prediabetic (n = 28), and diabetic (n = 23) groups. Plaque color grade was defined as 1 (light yellow), 2 (yellow), or 3 (intense yellow) based on angioscopic findings. The number of yellow plaques (NYPs) per vessel and maximum yellow grade (MYG) were compared among the groups.
RESULTS
Mean NYP and MYG differed significantly between the groups (P = 0.01 and P = 0.047, respectively). These indexes were higher in prediabetic than in nondiabetic patients (P = 0.02 and P = 0.04, respectively), but similar in prediabetic and diabetic patients (P = 0.44 and P = 0.21, respectively). Diabetes and prediabetes were independent predictors of multiple yellow plaques (NYPs ≥2) in multivariate logistic regression analysis (odds ratio [OR] 10.8 [95% CI 2.09–55.6], P = 0.005; and OR 4.13 [95% CI 1.01–17.0], P = 0.049, respectively).
CONCLUSIONS
Coronary atherosclerosis and plaque vulnerability were more advanced in prediabetic than in nondiabetic patients and comparable between prediabetic and diabetic patients. Slight or mild disorders in glucose metabolism, such as prediabetes, could be a risk factor for CAD, as is diabetes itself.
doi:10.2337/dc12-1635
PMCID: PMC3579367  PMID: 23223344
19.  Subclinical coronary atherosclerosis identified by coronary computed tomographic angiography in asymptomatic morbidly obese patients 
Heart International  2010;5(2):e15.
Obesity is a common public health problem and obese individuals in particular have a disproportionate incidence of acute coronary events. This study was undertaken to identify coronary artery lesions as well as associated clinical features, risk factors and demographics in patients with a body mass index (BMI) >40 kg/m2 without known coronary artery disease (CAD). Morbidly obese subjects were prospectively recruited to undergo coronary computed tomographic angiography (CCTA) using a dual-source computed tomography (CT) system. CAD was defined as the presence of any atherosclerotic lesion in any one coronary artery segment. The presence, location, and severity of atherosclerosis were related to patient characteristics. Forty-one patients (28 women, mean age, 50.4±10.0 years, mean BMI, 43.8±4.8 kg/m2) served as the study population. Of these, 25 patients (61%) had at least one coronary stenosis. All but 2 patients within the CAD cohort had coronary artery calcium (CAC) scores >0, and most plaques identified (75.4%) were non-calcified. There was a predilection of calcified and non-calcified atherosclerosis involving the left anterior descending (LAD) coronary artery compared with other coronary segments. Univariate predictors of CAD included older age, dyslipidemia, and diabetes. In this preliminary study of young morbidly obese patients, CCTA detected a high prevalence of calcified and non-calcified CAD, although the later predominated.
doi:10.4081/hi.2010.e15
PMCID: PMC3184688  PMID: 21977300
computed tomography; morbid obesity; risk factors; atherosclerosis.
20.  Computed tomography coronary angiography in patients with acute myocardial infarction and normal invasive coronary angiography 
Background
Three to five percent of patients with acute myocardial infarction (AMI) have normal coronary arteries on invasive coronary angiography (ICA). The aim of this study was to assess the presence and characteristics of atherosclerotic plaques on computed tomography coronary angiography (CTCA) and describe the clinical characteristics of this group of patients.
Methods
This was a multicentre, prospective, descriptive study on CTCA evaluation in thirty patients fulfilling criteria for AMI and without visible coronary plaques on ICA. CTCA evaluation was performed head to head in consensus by two experienced observers blinded to baseline patient characteristics and ICA results. Analysis of plaque characteristics and plaque effect on the arterial lumen was performed. Coronary segments were visually scored for the presence of plaque. Seventeen segments were differentiated, according to a modified American Heart Association classification. Echocardiography performed according to routine during the initial hospitalisation was retrieved for analysis of wall motion abnormalities and left ventricular systolic function in most patients.
Results
Twenty-five patients presented with non ST-elevation myocardial infarction (NSTEMI) and five with ST-elevation myocardial infarction (STEMI). Mean age was 60.2 years and 23/30 were women. The prevalence of risk factors of coronary artery disease (CAD) was low. In total, 452 coronary segments were analysed. Eighty percent (24/30) had completely normal coronary arteries and twenty percent (6/30) had coronary atherosclerosis on CTCA. In patients with atherosclerotic plaques, the median number of segments with plaque per patient was one. Echocardiography was normal in 4/22 patients based on normal global longitudinal strain (GLS) and normal wall motion score index (WMSI); 4/22 patients had normal GLS with pathological WMSI; 3/22 patients had pathological GLS and normal WMSI; 11/22 patients had pathological GLS and WMSI and among them we could identify 5 patients with a Takotsubo pattern on echo.
Conclusions
Despite a diagnosis of AMI, 80 % of patients with normal ICA showed no coronary plaques on CTCA. The remaining 20 % had only minimal non-obstructive atherosclerosis. Patients fulfilling clinical criteria for AMI but with completely normal ICA need further evaluation, suggestively with magnetic resonance imaging (MRI).
Electronic supplementary material
The online version of this article (doi:10.1186/s12872-016-0254-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s12872-016-0254-y
PMCID: PMC4855362  PMID: 27142217
Acute myocardial infarction; Normal coronary arteries; Computed tomography coronary angiography; MINCA
21.  Clinical indicators of periodontal disease in patients with coronary heart disease: A 10 years longitudinal study 
Objectives: There is evidence about a possible relationship existing between periodontal diseases and coronary heart disease. The aim of the present longitudinal study was to investigate the changes in periodontal evolution after etiological periodontal treatment, comparing a healthy control group with another having coronary heart disease. Study Design: The study included initially 55 patients of which 44 finished it. They were placed into two groups: Healthy Control Group (HCG) n =9, and Coronary Heart Disease Group (CHDG) n=35. The gingival level (GL), probing depth (PD), clinical attachment level (CAL), plaque index (PI) and bleeding on probing (BOP) were measured to compare the periodontal status in both groups. The patients were examined and etiological periodontal treatment was performed and they were then examined at the end of 1 and 10 years. Statistical method: A one way-ANOVA and a MR-ANOVA were established; significance p<0.05. Results: No significant differences between both groups were detected on the first visit (p>0.5). However, at the second visit the CHDG presented a significantly higher PD (p<0.05) and PI (p<0.01). CHDG patients gradually increase PD through time and in comparison to the control group (p<0.041). CHDG patients present a significantly higher CAL loss (p<0.0385) and a significant increase in PI (p<0.0041) at the end of one year, while on the third visit no significant differences were detected in any of these indices. Likewise, a similar fact can be observed on evaluating BOP at the end of ten years causal treatment, a smaller decrease in the cardiac group was observed in regards to the initial values (p<0.001). Conclusion: Patients with coronary heart disease showed a worse evolution of periodontal indices than healthy ones, when referring to probing depth, plaque index and bleeding on probing index.
Key words:Attachment loss, coronary heart disease, periodontal disease, risk factors.
doi:10.4317/medoral.17848
PMCID: PMC3476017  PMID: 22173486
22.  Intravascular ultrasound imaging of angiographically normal coronary arteries: a prospective study in vivo. 
British Heart Journal  1994;71(6):572-578.
Intravascular ultrasound imaging (IVUS) was performed to elucidate the discrepancy between clinical history and angiographic findings and to measure the diameter and area of the lumen of the normal left coronary artery in 55 patients who presented with chest pain but had normal coronary angiograms. The left coronary artery (LCA) was scanned with a 4.8F, 20 MHz mechanically rotated ultrasound catheter at 413 sites. Atherosclerotic lesions were identified at 72 (17%) sites in 25 patients. The mean (SD) (range) plaque area was 5.55 (3.56) mm2 (2-26 mm2) and it occupied 28.8 (9.6)% (13-70%) of the coronary cross sectional area. Calcification was detected at 24 (33%) atherosclerotic sites in nine patients. The correlation coefficients for the lumen dimensions measured at normal sites by IVUS and by angiography were r = 0.93 (SEE = 0.43) mm for lumen diameter and r = 0.89 (SEE = 4.27) mm2 for lumen area (both p < 0.001). 16 of the 30 patients in whom no atherosclerotic plaques were detected in the LCA lumen by IVUS had no risk factors of coronary artery disease. The cross sectional area of 90 consecutive images of left main coronary artery (LMCA), proximal left anterior descending coronary artery (proximal LAD), and mid LAD was measured in these 16 subjects. The mean (SEM) areas at end diastole were LMCA 17.33 (7.98) mm2; proximal LAD 13.56 (5.85) mm2; mid LAD 9.75 (4.67) mm2. During the cardiac cycle the cross sectional area changed by 10.2 (4.0)% in the LMCA, by 8.3 (4.7)% in the proximal LAD, and by 9.8 (4.0)% in the mid LAD. In 11 patients with plagues the change in cross sectional area in plague segments (5.8(3.1)%) was significantly lower than in the segments from patients without plagues (p < 0.001). Lumen area reached a maximum in early diastole rather than in late diastole. IVUS can imagine atherosclerotic lesions that are angiographically silent; it also provides detailed information about plague characteristics. The variation in coronary cross sectional area during the cardiac cycle should not be ignored during quantitative analysis. Maximum dimensions in normal segments are reached in early diastole. Further studies are needed to clarify the clinical significance of atherosclerosis detected by IVUS in patients presenting with chest pain but normal coronary angiography.
Images
PMCID: PMC1025457  PMID: 8043342
23.  Transesophageal Echocardiographic Detection of Thoracic Aortic Plaque Could Noninvasively Predict Significant Obstructive Coronary Artery Disease 
Objective
Previous pathologic and roentgenographic studies have suggested a relation between aortic plaque and coronary artery disease but have lacked clinical utility. The study was undertaken to elucidate whether atherosclerotic aortic plaque detected by transesophageal echocardiography can be a clinically useful marker for significant obstructive coronary artery disease.
Methods
Clinical and angiographic features and intraoperative transesophageal echocardiographic findings were prospectively analyzed in 131 consecutive patients (58 women and 73 men, aged 17 to 75 years [mean 54±12]) undergoing open heart surgery. Significant obstructive coronary artery disease was defined as > or = 50% stenosis of > or = 1 major branch.
Results
Seventy-six (58%) of 131 patients were found to have obstructive coronary artery disease. In 76 patients with significant coronary artery disease, 71 had thoracic aortic plaque. In contrast, aortic plaque existed in only 10 of the remaining 55 patients with normal or minimally abnormal coronary arteries. The presence of aortic plaque on transesophageal echocardiographic studies had a sensitivity of 93%, a specificity of 82% and positive and negative predictive values of 88% and 90%, respectively, for significant coronary artery disease. There was a significant relationship between the degree of aortic intimal changes and the severity of coronary artery disease (r=0.74, P<0.0001). Multivariate logistic regression analysis of patient age, sex, risk factors of cardiovascular disease and transesophageal echocardiographic findings revealed that atherosclerotic aortic plaque was the most significant independent predictor of coronary artery disease.
Conclusion
This study indicates that transesophageal echocardiographic detection of atherosclerotic plaque in the thoracic aorta is useful in the noninvasive prediction of the presence and severity of coronary artery disease.
doi:10.3904/kjim.1999.14.2.20
PMCID: PMC4531913  PMID: 10461421
Transesophageal echocardiography; Aortic plaque; Coronary artery disease
24.  Khat chewing and cardiovascular risk profile in a cohort of Yemeni patients with angiographically documented coronary artery disease 
Heart Asia  2012;4(1):164-167.
Objective
We sought to explore the prevalence of khat chewing and cardiovascular risk profile in a cohort of Yemeni patients with angiographically documented coronary artery disease (CAD).
Methods
We enrolled 100 consecutive Yemeni patients who underwent elective coronary catheterisation. Patients were considered eligible for enrolment if they had angiographically documented significant CAD (>50% obstruction). History of khat chewing was obtained and recorded at the time of presentation. Coronary angiography was performed using the standard technique. Reference vessel diameter and the per cent diameter stenosis were measured using quantitative coronary analysis. Patients were classified according to the number of sizable coronary arteries affected by significant stenosis into three groups: single-vessel disease, two-vessel disease and multi-vessel disease groups.
Results
The mean age was 54.7±11.8 years (16% females); 86% were khat users, 46% had single-vessel disease, 36% had two-vessel disease and 18% had multi-vessel disease. Fifty-four per cent were smokers, 11% were diabetic and 15% were hypertensive. The mean body mass index was 24.7±3.6, the mean serum low-density lipoprotein cholesterol was 129±41 mg/dl, whereas the mean serum triglyceride level was 187±90 mg/dl; the mean serum high-density lipoprotein cholesterol was 38±11 mg/dl. No correlation was found between the extent of CAD and any of the clinical, echocardiographic or laboratory data.
Conclusions
In Yemeni patients undergoing elective coronary angiography, khat use was highly prevalent, whereas several classic risk factors were relatively infrequent. None of the risk factors or khat use differed substantially with the extent of CAD.
doi:10.1136/heartasia-2012-010205
PMCID: PMC4832631  PMID: 27326057
Coronary Artery Disease
25.  Renal Artery Stenosis and Its Predictors in Hypertensive Patients Undergoing Coronary Artery Angiography 
Iranian Journal of Radiology  2011;8(4):235-240.
Background
Renal artery stenosis (RAS) has been increasingly recognized in the recent years, especially in patients with coronary artery disease (CAD). RAS affects the patients with hypertension (HTN), but the exact prevalence is not known.
Objectives
This study was performed to determine the prevalence and to identify the predictors of RAS in hypertensive patients undergoing coronary artery angiography.
Patients and Methods
In a cross-sectional study from August 2008 to August 2009, 481 patients with HTN and suspected CAD underwent selective coronary and renal angiography for screening and predicting RAS. RAS was defined as a higher than 50% stenosis in the renal artery lumen. Multivariate analysis of factors associated with the presence of RAS were examined using a logistic regression model.
Results
The mean ± standard deviation of age was 59.25 ± 10.81 years and 50.3% were men. According to angiographic data, 425 patients (88.4%) had CAD, while 56 (11.6%) had normal coronary arteries. RAS was seen in 94 (22%) patients with CAD. The multivariate logistic regression analysis identified only age (P < 0.001) and the number of significant coronary lesions (P < 0.001) as independent predictors of RAS. Gender, smoking, congestive heart failure, diabetes mellitus (DM), hyperlipidemia (HLP) and body mass index (BMI) were not independent predictors.
Conclusions
This study suggests that in the management of patients with RAS, risk factors should most likely be considered as beneficial. In addition, the clinical and angiographic features are helpful in predicting its presence in elderly patients with CAD.
doi:10.5812/iranjradiol.4553
PMCID: PMC3522365  PMID: 23329947
Renal Artery Obstruction; Coronary Artery Disease; Hypertension; Angiography

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